Taxol is a naturally occurring diterpenoid which has demonstrated great potential as an anti-cancer drug. Taxol, shown below as compound 1, can be isolated from the bark of the western yew, Taxus brevifolia, and is also found in several other yew species such as T. baccata and T. cuspidata. For further information regarding taxol, see Kingston et al., U.S. Pat. No. 5,059,699. All patents, articles, and other documents cited herein are incorporated by reference as if reproduced in full below. ##STR1##
Taxol almost: always co-occurs with the closely related compound cephalomannine, shown below as compound 2. Due to their close structural similarity, the separation of taxol from cephalomannine is a very difficult one. See Wani et al., "Plant Antitumor Agents. VI. The Isolation and Structure of Taxol, A Novel Antileukemic and Antitumor Agent from Taxus brevifolia," J. Am Chem. Soc. 93, 2325(1971); Powell et al., "Cephalomannine; A New Antitumor Alkaloid from Cephalotaxus mannii," J. Chem. Soc. Chem. Commun. 102 (1979); Miller et al., "Antileukemic Alkaloids from Taxus wallichiana Zucc," J. Org. Chem. 46, 1469 (1981). The only practical methods developed thus far for the separation involve careful and demanding chromatography or dihydroxylation of the taxolcephalomannine mixture followed by flash chromatography affording pure taxol, and cephalomannine-diols (a mixture of diastereomers, shown below as compound 29). See Kingston et al., "Modified Taxols, 7. A Method for the Separation of Taxol and Cephalomannine.") Nat. prod. 55, 259 (1992). ##STR2##
Since taxol is very scarce, a procedure to convert the resulting cephalomannine-diols to taxol would prove valuable because it would increase the supply of taxol. A method to make taxol from cephalomannine while avoiding the need to separate cephalomannine from taxol, would also be desirable.
No previous work on a direct conversion of cephalomannine to taxol has been reported. An indirect route is available through the work of Magri et al., in Journal of Organic Chemistry, Vol. 51, p. 3239, 1986, who reported that taxol can be converted to baccatin III, shown below as compound 3, by treatment with tetrabutylammonium borohydride in dichloromethane. It has been discovered that this process works equally well with cephalomannine, so a pathway exists to prepare baccatin III 3 from cephalomannine. ##STR3##
Baccatin III 3 can be converted to taxol by one of several published pathways. See, for example, Holton, R., "Method for Preparation of Taxol Using an Oxazinone," U.S. Pat. No. 5,015,744; Denis et al., "Highly Efficient Practical Approach to Natural Taxol," J. Am. Chem. Soc. 110, 5917(1988); Mangatal et al., "Application of the Vicinal Oxyamination Reaction with Asymmetric Induction to the Hemisynthesis of Taxol and Analogues," Tetrahedron 45, 4177(1989); Denis et al., "Process for Preparing Taxol," U.S Pat. No. 4,924,011 (1990); Colin et al., "Process for the Preparation of Taxol and 10-deacetyltaxol," U.S. Pat. No. 4,857,653 (1989); Ojima et al., "New and Efficient Approaches to the Semisynthesis of Taxol and its C-13 Side Chain Analogs by Means of b-lactam Synthon Method," Tetrahedron, 48, 6985-7012 (1992); Georg et al., "An Efficient Semisynthesis of Taxol from (3R,4S)-N-Benzoyl-3-[(t-butyldimethylsily)oxy]-4-phenyl-2-azetidinone and 7-(Triethylsilyl)baccatin III," Bioorg. Med. Chem. Lett., 3, 2467-2470 (1993); Denis et al, "Taxotere by Esterification with Stereochemically "Wrong" (2S,3S)-Phenylisoserine Derivatives," Tetrahedron Lett., 35, 105-108 (1994); Commercon et al., "Improved Protection and Esterification of a Precursor of the Taxotere and Taxol Side Chains," Tetrahedron Lett., 33, 5185-5188 (1992).
Hence, cephalomannine can be converted to taxol through baccatin III 3, by treatment of cephalomannine with, by way of non-limiting example, tetrabutylammonium borohydride in the presence of dichloromethane. However, this process requires the synthesis of the .beta.-phenylisoserine side-chain of taxol in enantiomerically pure form, and the coupling of the side-chain to baccatin III 3 does not proceed quantitatively.
Because of the promising clinical activity of taxol against various types of cancer, the preparation of analogues of taxol is an important endeavor, especially in view of the previously mentioned limited supply of taxol. See McGuire et al., "Taxol: A Unique Antineoplastic Agent with Significant Activity in Advanced Ovarian Epithelial Neoplasms," Ann, Intern. Med. 111: 273-279 (1989); Holmes et al., "Phase II Trials of Taxol, an Active Drug in the Treatment of Metastatic Breast Cancer," J. Natl. cancer Inst, 83: 1797-1805 (1991).
It is believed that the preparation of taxol analogues will result in the synthesis of compounds with comparable or greater potency than taxol (thus reducing the need for the drug), superior bioavailability, or having less undesirable side effects. Indeed, the synthesis of the taxol analogue taxotere, which differs from taxol only in the nature of the N-acyl substituent and the absence of the 10-acetyl group, indicates the usefulness of this approach, since taxotere is reported to be approximately twice as active as taxol in some assays (although taxol is believed to be more effective in other systems than taxotere). See Gueritte-Voegelein et al., "Chemical Studies of 10-Deacetylbaccatin III. Hemisynthesis of Taxol Derivatives," Tetrahedron 42: 4451-4460 (1986); Ringel et al., "Studies with RP56976 (Taxotere) A Semisynthetic Analogue of Taxol," J. Natl Cancer Inst. 83: 288-291 (1991).
A large number of taxol analogs have antitumor properties as shown by their ability to inhibit the disassembly of microtubules. See "Relationships between the Structure of Taxol Analogues and Their Antimitotic Activity," Journal of Medicinal Chemistry, Vol. 34, pp. 992-998 (1991); "Biologically Active Taxol Analogues with Deleted A-Ring Side Chain Substituents and Variable C-2' Configurations," Journal of Medicinal Chemistry, Vol. 34, pp. 1176-1184, (1991); "Synthesis and Evaluation of Some Water-Soluble Prodrugs and Derivatives of Taxol with Antitumor Activity," Journal of Medicinal Chemistry, Vol. 35, pp. 145-151, (1992). The foregoing articles demonstrate the effectiveness of taxol analogs as antitumor agents.
Nonetheless, many taxol analogs have shown reduced biological activity when compared to taxol. Thus, there remains a need for taxol derivatives or compounds having similar biological activities to taxol. There is a corresponding need for methods to prepare taxol derivatives and taxol congeners.
There is also a need to prepare taxol from naturally occurring mixtures, and more particularly, there is a need to convert cephalomannine, or mixtures comprising cephalomannine, to taxol.
There is also a need for better methods of treating cancer, and more particularly of treating cancer with taxol analogs.